The present invention relates to compounds useful as immunosuppressive, anti-inflammatory and anticancer agents. The compounds have good aqueous solubility and convert to biologically active compounds in vivo.
Boyd, G. V. and Heatherington, K., J. Chem. Soc. Perkin I 2523-2531 (1973).
Ferrier, R. J., in Carbohydrate Chemistry, Kennedy, J. F., Ed., Clarendon Press, Oxford (1990).
Garver, L. C. et al., J. Am. Chem. Soc. 104:867 (1982).
Gleichmann, E. et al., Immunol. Today 5:324 (1984).
Hormi, O. E. O. and Nasman, J. H., Syn. Commun. 16:69 (1986).
Kocienski, P. J., Protecting Groups, Georg Thieme Verlag, Stuttgart (1994).
Korngold, R. and Sprent, J., J. Exp. Med. 148:1687 (1978).
Kupchan, S. M. et al., J. Am. Chem. Soc. 94:7194 (1972).
Kupchan, S. M. et al., U.S. Pat. No. 3,005,108 (1977).
Lipsky, P. E. et al., U.S. Pat. No. 5,294,443 (1994).
Ma, P-C. et al., J. Chin. Pharm. Sci. 1:12 (1992).
Mori, S. et al., Tetrahedron 47(27):5051-5070 (1991).
Morris, R. E., Transplant Proc. 23(6):2722-2724 (1991).
Morris, R. E. et al., Transplant Proc. 23(1):238-240 (1991).
Murase, N. et al., Transplantation 55:701 (1993).
Ono and Lindsey, J. Thor. Cardiovasc. Surg. 57(2):225-29 (1969).
Pu, L. et al., Zhongguo Yaoli Xuebao 11:76 (1990).
Wang, J. and Morris, R. E., Transplantation Proc. 23:699 (1991).
Yu et al., Acta Pharmaceutica Sinica 27(11):830-836 (1992).
Zheng, J. et al., Zhongguo Yixue Kexueyuan Xuebao 13:391 (1991).
Zheng, J. et al., Zhongguo Yixue Kexueyuan Xuebao 16:24 (1994).
Immunosuppressive agents are widely used in the treatment of autoimmune disease and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD), a condition in which transplanted marrow cells attack the recipient""s cells. Common immunosuppressive agents include azathioprine, corticosteroids, cyclophosphamide, methotrexate, 6-mercaptopurine, vincristine, and cyclosporin A. In general, none of these drugs are completely effective, and most are limited by severe toxicity. For example, cyclosporin A, a widely used agent, is significantly toxic to the kidney. In addition, doses needed for effective treatment may increase the patient""s susceptibility to infection by a variety of opportunistic invaders.
A number of compounds derived from the Chinese medicinal plant Tripterygium wilfordii (TW) have been identified as having immunosuppressive activity, e.g. in the treatment of autoimmune disease, and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD), a condition in which transplanted marrow cells attack the recipient""s cells. See, for example, coowned U.S. Pat. No. 6,150,539 (Triptolide prodrugs having high aqueous solubility), U.S. Pat. No. 5,962,516 (Immunosuppressive compounds and methods), U.S. Pat. No. 5,843,452 (Immunotherapy composition and method), U.S. Pat. No. 5,759,550 (Method for suppressing xenograft rejection), U.S. Pat. No. 5,663,335 (Immunosuppressive compounds and methods), and U.S. Pat. No. 5,648,376 (Immunosuppressant diterpene compound), and references cited therein. Such compounds have also been reported to show anticancer activity. See, for example, Kupchan et al., 1972, 1977, as well as copending and coowned U.S. application Ser. No. 09/766,156.
The administration and therapeutic effectiveness of these compounds have been limited, however, by their low water solubility. This problem has been addressed by formulating the compounds in mixtures of ethanol and polyethoxylated castor oil (e.g., xe2x80x9cCREMOPHOR EL(trademark)xe2x80x9d), allowing subsequent dilution in saline for intravenous administration. However, such formulations have suffered from high toxicity, due to the high concentration of solubilizing agent required to dissolve these compounds. For example, the ratio of solubilizing agent (ethanol plus xe2x80x9cCREMOPHOR EL(trademark)xe2x80x9d) to triptolide in such formulations is typically on the order of 1000:1 or greater, due to the poor solubility of triptolide (Morris, 1991; Morris et al., 1991). Standardization of dosage amounts is also more problematic with a suspension than with a solution.
It is therefore desirable to provide immunosuppressive compounds having comparatively low toxicity and improved water solubility. Ideally, such compounds would show immunosuppressive activity in their water soluble form, or would be convertible to an immunosuppressive form in vivo.
In one aspect, the invention provides compounds which are useful as prodrugs for immunosuppressive, anti-inflammatory and anticancer therapy. The compounds are derivatives of triptolide having hydrophilic substituents, represented by structures I-III, as shown and described below. The compounds possess greater water solubility than the non-derivatized parent compound, triptolide, and, in most cases, are effective to hydrolytically convert to the parent compound in vivo.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.